Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits - PubMed (original) (raw)

doi: 10.1371/journal.pgen.0030115.

Serena Sanna, Wei-Min Chen, Manuela Uda, Giuseppe Albai, James Strait, Samer Najjar, Ramaiah Nagaraja, Marco Orrú, Gianluca Usala, Mariano Dei, Sandra Lai, Andrea Maschio, Fabio Busonero, Antonella Mulas, Georg B Ehret, Ashley A Fink, Alan B Weder, Richard S Cooper, Pilar Galan, Aravinda Chakravarti, David Schlessinger, Antonio Cao, Edward Lakatta, Gonçalo R Abecasis

Affiliations

Angelo Scuteri et al. PLoS Genet. 2007 Jul.

Abstract

The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 x10(-7)), hip circumference (p = 3.4 x 10(-8)), and weight (p = 9.1 x 10(-7)). In Sardinia, homozygotes for the rare "G" allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common "A" allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 x 10(-6)). Homozygotes for the rare "A" allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common "G" allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496) and in Hispanic Americans (N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001), and hip circumference (p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare "A" allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for the more common "G" allele. In summary, we have completed a whole genome-association scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.

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Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Negative Log of _p_-Value for Single Marker Association Analysis with Three Obesity-Related Traits

Locations of PFKP and FTO genes are highlighted.

Figure 2

Figure 2. Association Results and LD Patterns in Region Surrounding the FTO Gene

(A) Summary of the association between SNPs in the region and BMI. The SNP showing strongest association (rs9930506) is highlighted. Other SNPs are colored according to their degree of disequilibrium with rs9930506 ranging from high (red), to intermediate (green), to low (blue). Transcripts are indicated at the bottom of the graph, with an arrow indicating transcript direction. (B) Summary of the patterns of disequilibrium in the region in Sardinia and in two of the HapMap populations (CEU and YRI) [55]. The grey bar marks the region of association and facilitates comparisons between the panels.

Figure 3

Figure 3. Association Results and LD Patterns in Region Surrounding the PFKP Gene

(A) Summary of the association between SNPs in the region and BMI. The SNP showing strongest association (rs6602024) is highlighted. Other SNPs are colored according to their degree of disequilibrium with rs6602024, ranging from high (orange) to low (blue). Transcripts are indicated at the bottom of the graph, with an arrow indicating transcript direction. (B) Summary of the patterns of disequilibrium in the region in Sardinia and in two of the HapMap populations (CEU and YRI) [55]. The grey bar marks the region of association and facilitates comparisons between the panels.

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